Substituted styryl, and thienylethenyl, pyridylethenyl sulfonylureas and method of treating diabetes



nited States P te SUBSTITUTED STYRYL, AND THIENYLETHENY L,

PYRIDYLETHENYL SULFONYLUREAS AND METHOD OF TREATING DIABETES William M. McLamore, Kew Gardens, and Gerald D. Laubach, Jackson Heights, N.Y., assignors to Chas. Pfizer 8: Co., Inc., New York, N.Y., a corporation of Delaware No Drawing. Filed Sept. 2,1958, Ser. No. 758,559

7 Claims. (Cl. 167--65) This invention relates to new and useful aralkenesulfonylureas. Moreover,-it is particularly concerned with N-ara1kenesulfonyl-N substituted ureas, such' as- N-(2- arylethene-l-sulfonyl)aNf-alkylor arylureas, 'and the 2,979,437. f Patented Apr. 11, 1 961 2 polar organic solvent with an appropriate ,N,N-diaryl-N'- substituted urea in accordance with the novel procedure described and claimed in copending US. patent application Ser. No. 711,570, filed on January 28, 1958, by the present co-inventors. i

' The starting materials required for preparing the compounds of this invention are either commercially available or else they are easily prepared in accordance with the method disclosed by F.;G. Bordwell et al. in the Journal of the American Chemical Society, vol. 68, p.

, 139 (1946), whereby an ara-lkene comp'ound'is reacted with dioxane-sulfot'rioxideto afford good yields of the corresponding 2-arylethene-1-sulfonic acids. The monoalkali metal; or alkaline-earth metal salts of these sulforiic acids are obtained by the addition of an aqueous solution of the appropriate metallic carbonate or hydroxide to the originalsulfonation mixture; the salts which like. These compounds are of especial value due to the v hypoglycemic activity which they exhibit. There is also included within the scope of this invention pharmaceutical compositions comprising these aralkenylsulfonylureas as the essential active ingredient together; with diluentform are easily isolated from the mixture and theycan be subsequently converted to the corresponding aralkenesulfonyl chlorides by treatment .with phosphorus pentachloride. .The parent aralkenes (arylethenes), which are the ultimate starting materials for this particular series of.reaction s, are-for the most part commercially available with the exception of those aralkenes of the thiophene 'series'; the latter compounds may be easily prepared in accordancewith the methods discussed by Hartough on page 164 o f'his authoritative textbook, Thiodimethylphenyl, 3 ,4 dichloropheny1} 3-chloro-p-tolyly5- chloro-Z-thinyl, 5-bromo-2-thienyl, '5 methyl-2-thienyl, 4-methyl-2-thienyl, 5-t-butyl-2-thienyl,'- 2,5-dimethyl-3- thienyl, 2,5-dichloro-3-jthienyl, 5-chloro-2-methyl-3-thienyl, 6-rnethyl-2-pyridyl and '4,6-dimethyl-2-pyridyl,' 6- 'amino-3-pyridyl, and the like; and 'R--is "alkyl having fromone to ten carbon atoms, alkenyl having from three to eight carbon atoms, cycloalkyl 'havingfrom three to six carbonato'ms andcycloalkylalkyl having from four to nine carbon atoms, or itis-an aryl moiety as previously definedforR; preferred R-' aryl moieties include phenyl, p-chlorophenyl, 'p-b'romophe'nyl,

p-nitrophenyl, p-acetylaminophenyl, p-tolyl, p-anisyl, 2-f

thienyl,t 2 .pyridyl, and the like. .Examples of such. comenylethene-l-sulfonyl)-Nf-n-propylure a. I a a. The advantages aiforded by the 'aralkenesulfonylureas of this inventionare manifold: they may be. administered orally, thus eliminating th e parenteral routev which is often painful and irritating;.the y lower, blood sugar levels to aneilective degree in animals, including humans," for a siistained period offitime; their toggle side eiiect's'are eithenminimal or absent; they present no eyidence of kidney damage or'crystalluria; and they are readily 10btained in good yields from commercially available starting materialsby either of tworelatively simple methods,

as discussed hereinafter. t

For instance, regarding methods tor preparingpjthe compoundsj of this invention, an -:appropriate-.aralkenesulfonamide can be reacted, with the desired organic isocyanate in accordance with a modification of theclas- Society, 1951, page 1258) described in detail in some of the examples "of this specification; 7;. alternatively, these compounds may also be=synthesized by reacting a"mono "alkaliimetal saltf or an alkaline-earth metalv salt of the corresponding' aralkenesulfonamider in Zaireaction; inert I sical procedure (F. Kurzetg Journal of the Chemical.-

, starch adapted to swell rapidly 7 thereby disintegratingsaid tablet.

phene and its Derivatives, Inter'science Publishers, Inc},

New York, N.Y. (1952).

The N,N diaryl N'-monosubstituted ureas may be readily preparedby means'of the following reaction,

which is illustrated below, wherein R" is an aryl moiety,

such as phenyl, p-chlorophenyl, .p-bromophenyl, p -nitrophenylfp-tolyl, p' a'nisyl, wriaphthyl and fienaphthyl, in accordance with the procedure described by Reudel in the Recueil'des Travaux Chimiques des Pays-Bas, Vol.33,

The two reactants stated in the above equation are either commercially available or else'th'ey can easily beprepared by those skilled in the art from readily available starting materials according v to classical organic procedures such as thosepresented by Houben-Weyl in Die Methoden der organischen Ohemie, Fourth Edition, vol. 8,- p. 117 (1952). t i

' The aralkenesulfonylureas of this invention may be administered either aloneor 'in combinationwith a diluent amount of a pharmaceutically acceptable inert carrier; -In general, the usual dosage for administering these compounds to' animals is in' the range 'ofapproximately 0.25-2.5 g. per day in the order of about one to about fivedoses. However, this will vary somewhat with the weight of, the subject beingjtreated;v ordinarily,

. about 4.0-40 mgg/kg. of body weight per day is employed;

Inthis connection, itshould be noted that'the aforementioned. requisite dosage is" substantially below the LD value for thesecompounds. v. l

For purposes'of oral administration, these compounds may be administered in the formJof hardv or soft-filled gelatin capsules containing an inert filler such as lactose or milk sugar; or they may be administered in the form of elixers, syrupsor aqueous suspensions, such carriers containing sweetening and/ or flavoring agents. The preferredfmethod of oral administrationcomprises theme of a rapidly disintegrablepalatabletablet. A'preferred form of sucha tablet comprises a plurality of compressed granules containing a sweetening agent bound there within by a sugar alcohol and dispersed in the interstices between said granules, a flavoring agent and a hydrophilic on contact with water,

anemia-e" This invention isfurther. il1ustrates1,..by hetnll wing.

examples, which are not to. be considered as imposing any limitations on the scope thereof.

formamide was added to a chilled solution consisting of 5,5 g. (0.030 mole) of B-styrenesulfonamide dissolved in 15 ml. of anhydrous triethylamine; the addition was carried out with constant agitation during the course of about fifteen minutes. The mildly exothermic reaction was completed by allowing it to stand at room temperature for about five days. The reaction mixture was then slowly added to 500 ml. of chilled 70% acetic acid during the course of about one-half hour with constant agitation being maintained throughout the addition. After this step was completed the crystalline material which had precipitated from solution was recovered by means of filtration and subsequently washed with 100 ml. of cold water. The crude material so obtained was then dissolved in 200 ml. of cold 5% sodium carbonate and the resulting solution was, immediately filtered in order to remove any insoluble gum. Isolation of the desired product from the resulting filtrate was then effectedby slowly adding 500 ml. of 20% aceticacid to the filtrate, whereupon precipitation of the crystalline material occurred. The product was then filtered; washed and subsequently air dried to alford pure N-(fl-styrenesulfonyl)-N'-n-butylurea, which melted at 1273-1288" C. after one recrystallization from chloroform-diethyl ether in the presence of charcoal.

v Analysis.Calcd. for C13H18N2O3S: C, 5530;11, 6.43; N, 9.92. Found: c, 55.36; H, 6.58; 9.78.

Example 11 The procedure described in Example I was followed except that 5.5 g. (0.030 mole) of {3-styrenesulfonamide dissolved in 15 ml. of anhydrous triethylamine and 3.0 g. (0.035 mole) of n-propyl isocyanate dissolvedin 10 ml. of anhydrous dimethylformamide are reacted to afford N- (B-styrene-sulfonyl)-N-n-propylurea, M.P; 157175.5 C

, Analysis.Calcd. for C H N O S: C, 53.71; H, 6.01; ,N, 10.49. Found: C, 52.62; H, 5.83; N, 10.05.

In the same manner, corresponding molar amountstof p-chloro-B-styrene-sulfonamide and p-chlorophenyl isocy-anate react to afford N-(p-chloro-;3-styrene-sulfonyl)- N'-p-chlorophenyl-urea similarly, p-bromo fi-styrenesulfonamide and cyclohexyl isocyanate react to afiord-N-(pbromo-B-styrenesulr'onyl)-N-cyclohexylurea. Moreover, when p-methyl-fi-styrenesulfonamide and p-anisyl isocyanate are reacted in accordance with this same procedure,

the product obtained is N(Prmethyl-fi-styrenesulfonyl)- Example III ,The procedure described in Example I is followed by reacting 5.5 g. (0.030 mole) of S-styrenesulfonamide in 15 ml. of triethylarnine and 2.0 g. (0.035 mole) of methyl isocyanate in 10 ml. of dimethylformamide to yield N- (B-styrenesulfonyl) -N-methylurea. In the same manner, corresponding molar amounts ofp-fiuoro-B-styrenesulfonamide and ethyl isocyanate react to yield N-(p-fiuoro-flr styrenesulfonyl)-l l-ethylurea. When p-chloro-p-styren'esulfonamide and n-propyl isocyanate react'in accordance with this procedure, the product is N-(p-chloro-fi styrene sulfonyl)-N'-n-propylurea, while p-brommB-st'yrenesulfonamide and n-butyl isocyanate react in the samemanner to afford N-(p-bromo-B-styrenesulfonyl)-N'-n-butylurea.

In the same manner, p-nitro-,B-styrenesulfonamide and t-butyl isocyanate react to afford N-(p-nitro-fl-styrenesulfonyl) -N'-t-b utylurea; p -acetylamino-B-styrenesulfonamide and n-amyl'isocyanatereact to afiord N-(p-acetyl- I amino-fi-styrenesulfonyl) -Nf-n-amylurea; p-methyl-B-sty cyclopentyl isocyanate react to afiord N-(E-chlo-ro-pmethyl-fl-styrenesulfonyl)-N-cyclopentylurea;

Examplel-V When 5.65 g. (0.030 mole) of Z-thienylethene-l-sulfonamide and 3.0. g. (0.035 mole) of n.-propyl isocyanate react in accordance with the procedure of Example I, the product is N-(Z-thienylethene-l-sulfonyl)-Nn-propylurea; and when corresponding-molar amounts of Z-thienylethene-l-sulfonamide and cyclohexyl isocyanate react in accordance with this same procedure. the procedure, the product is.N-(Z-thienylethene-l-sulfonyl)-N'- cyclohexylurea. In the same manner; corresponding molar amounts of 5-chloro-2rthienylethene-l-sulfonamide and allyl isocyanate react to afford N-(5-chloro-2- thienylethene 1 sulfonyl) N allylurea; 5 bromo- Z-thienylethene-l-sulfonamide and' 2-amylene isocyanate react to afi'ord N:(5-bromo-2fthieuylethene-l-sulfonyl)- N-2-amyleneurea; S-methyl 2 thienylethene-1-sulfonamide and Z-octyleneisocyanate react to afford N-(S- methyl-Z-thienylethene:l-sulfonyl)-N'-2 octyleneurea; 4- methyl-Z-thienylethene-l-sulfonamide and cyclopropylmethyl isocyanatez react to afford N-(4.-rnethyl-2-thienylethene-l-sulfonyl) -N'cyelopropylmethylurea; 5-t-butyl-2- thienylethene-l-sulfonamideand: cyclopentylethyl isocyanate react to aiford .N-(S-t-butyl-2-thienylethene-l-sulfonyl)-N cyclopentylethylurea; 2-.pyridylethene-l-sulfonamide and cyclohexylpropyl isocyan'ate react-to aiford N-(2-pyridylethene-l-sulfonyl)-N' cyclohexylpropylurea; 6-methyl-2-pyridylethene-l-sulfonamide and phenyl isocyanate react. to afford N-(6Tmethyl-2-pyridylethene-1- sulfonyl)-N'.-phenylurea; and 4,6-dimethyl-Z-pyridylethene-L-sulfonamide andp-chlorophenyl isocyanate react to afford ',fiy rpyridylethene-1-su1fony1)-N'-pchlorophenylurea. a I

Eatample V When, g; (0.030 mole) of p-styrenesulfonamide dissolved, in 15' ml. of triethylamine and 6.9 g. (0.035 mole) of p-bromophenyl isocyanate. dissolved in 10 ml. of dimethylformamide react in accordance with the procedure of Example Lthe product is N-(B-styrenesulfo-' renesulfonyl)-N' p-anisylurea; p acetylamino-B-styrenesulfonarnide and 2-thienyl isocyanate react'to afford N- (p-acetylamino-fl-styrenesulfonyl)-N2 thienylurea; and 'p-methyl-B-styrenesulfonamide' and 2-pyridyl isocyanate react to afford N-(p-methyl-fl-styrenesulfonyl)-N'-2-pyridylurea. I

0 Example VI fi've hours. The reaction mixture was then cooled to room temperature and diluted with 20 ml. of water. After the resulting aqueous solution had been made strongly alkaline with sodium hydroxide, it was extracted with diethyl ether in order to remove the diphenylamine by-product. The resulting aqueous layer was then successively separated and filtered, and the resulting filtrate was slowly poured into a chilled aqueous solution containing excess hydrochloric acid. The precipitated material so obtained was isolated by means of filtration, washed with cold water and subsequently air dried until constant weight was attained. This product proved to be N-(B-styrenesulfonyl)-N'-nbutylurea,.as attested to by its melting point and by the fact that no depression in the latter could be observed when it was admixed with an authentic sample prepared in accordance with Example I.

In the same manner, 3.2 g. (0.015 mole) of the monosodium salt of p-chloro-/3-styrenesulfonamide and 6.35 g.

(0.025 mole) of N,N-diphenyl-N'-n-propylurea are reacted in 10 ml. of anhydrous dimethylformamide to afford N-(p-chloro-B-styrenesulfonyl)-N-n-propylurea.

Example VII The procedure described in Example VI is followed except that corresponding molar amounts of other N,N- diphenyl-N-substituted ureas are used in. place of N,N- diphenyl-N'-n-butylurea or N,N-diphenyl-N'-n-propylurea. Thus, when 3.2 g. (0.015 mole) of the monosodium salt of p-chloro-B-styrenesulfonamide and 6.0 g. (0.025 mole) of N,N-diphenyl-N'-ethylurea in 10 ml. of anhydrous dimethylformamide react, the product is N- (p-chloro-fi-styrenesulfonyl)-N-ethylurea. In the same manner, corresponding molar amounts of the monosodium salt of p-fluoro-fi-styrenesulfonamide and N,N- diphenyl-N-methylurea react to yield N-(p-fiuoro-fi styrenesulfonyl)-Namethylurea. When the monosodium salt of p-bromo-fl-styrenesulfonamide and N,N-diphenyl- N'-phenylurea react, the product is N-(p-bromo-,8-styrenesulfonyl)-N'-pheuylurea; when N,N-diphenyl-N'-pchlorophenylurea is used in place of 'N,N-diphenyl-N'- phenylurea in this same reaction, the product is N-(pbromo-B-styrenesulfonyl)-N'-p-chlorophenylurea. In the same manner, the monosodium salt of p-nitro-flstyrenesulfonamide and N,N-phenyl-N'-p-tolylurea react to afford N-(p-nitro- 8-styrenesulfonyl)-N'-p-tolylurea; and the monosodium salt of p-chlo-ros-styrenesulfonamide and N,N-diphenyl-N-p-anisylurea react to afford N-(pchloro-fl-styrenesulfonyl) -N'-p-anisylurea.

Example VIII The procedure described in Example V1 is followed by reacting 5.85 g. (0.030 mole) of the monosodium salt of p-rnethyl-fi-styrenesulfo-namide and 10.15 g. (0.040 mole) of N,Ndiphenyl-N'-n-propylurea in 25 ml. of anhydrous dimethylformamide to yield N-(p-methyl-fistyrenesulfonyl)-N'-n-propylurea. In the same manner, corresponding molar amounts of the monosodium salt of p-methoxy-fl-styrenesulfonamide and N,N-diphenyl- N-t-butylurea react to afford N-(p-methoxy-;3-styrenesulfonyl)-N'-t-butylurea; the monosodium salt of 2,4- dimethyl-fl-styrenesulfonamide and N,'N-diphenyl-N'-cyclohexylurea react to afford N-(2,4-dirnethyl-5-styrenesulfonyl)-N'-cyclohexylurea; and the monosodium salt of 2,5-dimethyl-B-styrenesulfonamide and N,N-diphenyl-N'- cyclobutylurea react to aiford N-(2,5-dimethyl-[3-styrenesulfonyl)-N'-cyclobutylurea. When corresponding molar amounts of the monosodium salt of 3,4-dichloro-/3-styrenesulfonamide and N,N-diphenyl-N'-allylurea are reacted in accordance with the procedure described in Example VI, the product is N-(3,4-dichloro-B-styrenesulfonyl)-N'-allylurea; in the same manner, the monosodium salt of 3-chloro-p-methyl-fl-styrenesulfonamide and N,N- diphenyl-N'-2-amyleneurea react to afford N-(3-chloropmethyl-p-styrenesulfonyl) -N-2-amyleneurea.

- Example IX The .procedure of Example VI is followed by reacting 5.65 g. (0.030 mole) of the monosodiumsalt of 2'-thienyl ethene-l-sulfonamide and 10.15 g. (0.040 mole) of N,N- diphenyl-N'-cyclopropylurea in 25 m1. of anhydrous dimethylforrnamide to afford N-(Z-thienylethene-l-sulfonyl)-'N cyclopropylurea. In the same manner, corresponding molar amounts of the monosodium saltof 5- chloro-2-thienylethene-1-sulfonamide and N,N-diphenyl- N-cyclopropylmethylurea react to afford N-(S-chloro-Z- thienylethene-l-sulfonyl)-N-cyclopropylmethylurea; the monosodium salt of 5-bromo-2-thienylethene-1-sulfona mide and N,N-diphenyl-N-cyclopentylethylurea react to afford N-(5-bromo-2-thienylethene-l-sulfonyl)-N-cyclo pentylethylurea; the monosodium salt of 5-methyl-2-thienylethene-l-sulfonamide and N,N-diphenyl-N' cyclohexylpropylurea react to afford N-(5-methyl-2-thienylethenel-sulfonyl)-N'-cyclohexylpropylurea; and the monosodiurn salt of 4-methyl-2-thienylethene-l-sulfonamide and N,N-diphenyl-N'-cyclobutylurea react to afford N-(4- methyl 2 thienylethene 1 sulfonyl) N cyclobutylurea; when: the monosodium salt of 5-t-butyl-2-thienylethene-l-sulfonamide is employed in place of the corresponding salt of 4-methyl-2-thienylethene-l-sulfonamide in this same reaction, the product is N-(5-t-butyl-2-thienylethene-l-sulfonyl)-N'-cyclobutylurea.,

Example X I When 4.3 g. (0.015 mole) of the monosodium salt of 2,5-dichloro-3-thienylethene-l-sulfonamide and 7.75 g. (0.025 mole) of N,N-diphenylN'-n-heptylurea in 10 ml. of anhydrous dimethylformamide react in accordance with the procedure described in Example VI, the product is N-(2,5-dichloro-3-thienylethene-l-sulfonyl)-N'-n-heptylurea. In the same manner, the monosodium salt of 2,5-dimethyl-3-thienylethene-l-sulfonamide and N,N-diphenyl-N'-p-bromophenylurea react to alford N-(2,5-dimethyl 3 thienylethene 1 sulfonyl) N p bromophenylurea; the monosodium salt of 5-chloro-2-methyl-3- thienyl-ethene-l-sulfonamide and N,N-diphenyl-N-n-decylurea react to afford N-(5-chloro-2-methyl-3-thienylethene-l-sulfonyl)-N'-n-decylurea; the monosodium salt of 2-pyridylethene-l-sulfonamide and N,N-diphenyl-N- p-anisylurea react to aiford N-(2-pyridylethene-l-sulfonyl)-N-p-anisylurea; the monosodium salt of 6-methyl-2- pyridylethene-l-sulfonamide and N,N-diphenyl-N-nhexylurea react to afford N-(6-methyl-2-pyridylethene-l-sulfonyl)-N-n-hexylurea and the monosodium salt of 4,6- dimethyl-2-pyridylethene-1-sulfonamide and N,N-diphenyl-N-n-octylurea react to afford N-(4,6-dimethyl-2-pyridylethene-l -sulfo nyl) -N-n-octylurea.

Example Xl Tablets containing N-(B-styrenesulfonyl)-N-n-butylurea as the essential active ingredient together with a diluent amount of a pharmaceutically acceptable inert carrier are administered to each of a group of test subjects; an average dose of one to five tablets per day is administered orally, each tablet containing at least 500 mg. of active ingredient. The tablets employed are molded by compression in tablet machines. The diluent amount of a pharmaceutically acceptable, inert carrier consists of a sweetening agent, such as saccharin, bound therewithin by a sugar alcohol, such as lactose; it is moistened with alcohol and then forced through screens to form granules. There is then dispersed in the interstices between said granules a flavoring agent and a hydrophilic starch adapted to swell rapidly on contact with water, thereby disintegrating said tablet. The mixture is then completely dried before the tablets are punched. It is found that a-very good control of high blood sugar levels is obtained after oral administration of such N-(flstyrenesulfonyl)-N-n-butylurea containing tablets; the compound is rapidly absorbed when given by mouth, with maximum blood levels of the compound occurring Example XII The same procedure as described in Example XI is followed except that gelatin capsules are used in place of tablets. The capsules employed are either of the hard filled or soft elastic type. In the hard 'filled type, one part of the capsule is filled with at least 500 mg. of N-(fl-styrenesulfonyl)-N'-n-propylurea together with a diluent amount of an inert filler, such as lactose; the cap is then replaced and the capsule is ready for use. In the case of the soft elastic capsules, the same ingredients are deposited between layers of gelatin so prepared that when they are forced together under pressure they seal to alford an oval or spherical shaped capsule. In both cases, the results obtained .with respect to hypoglycemic activity are similar to those obtained with the tablet.

What is claimed is: 1. An aralkenesulfonylurea of the formula RCH=CHSO NHC0NHR' wherein R is an aryl moiety selected from the group consisting of phenyl, thienyl, pyridyl, substituted phenyl, substituted thienyl andsubstituted pyridyl, each substituent of such substituted moieties being selected from the group consisting of halogen, lower alkyl and lower alkoxy, nitro and acetylamino; and R is a member of the group consisting of alkyl having from one to ten carbon atoms, alkenyl having from three to eight carbon atoms, cycloalkyl having from three to six carbon atoms, cycloalkylalkyl having from four to nine carbon atoms, phenyl,

p-chlorophenyl, p-brornophenyl, p-nitrophenyl, p-acetylaminophenyl, p-tolyl, p-anisyl, Z-thienyl and 2-pyridyl.

2. The method of orally treating diabetes, which method comprises orally administering a compound of claim 1 to a diabetic patient, the daily dose amount ad-v References Cited in the file of thispatent FOREIGN PATENTS 70,259 Denmark Dec. 28, 1949 71,236 Norway Nov. 4, 1946 919,464 France Nov. 25, 1946 120,428

Sweden 5. Dec. 16, 1947 

1. AN ARALKENESULFONYLUREA OF THE FORMULA
 2. THE METHOD OF ORALLY TREATING DIABETES, WHICH METHOD COMPRISES ORALLY ADMINSISTERING A COMPOUND OF CLAIM 1 TO A DIABETIC PATIENT, THE DAILY DOSE AMOUNT ADMINISTERED BEING FROM ABOUT 4.0-40 MG./KG. OF BODY WEIGHT OF SAID PATIENT. 